This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid ...tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell–derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell–derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell–derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the
BRAF
-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the
RAS
-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0 cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term “Hürthle cell” is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell–derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm
2
). High-grade follicular cell–derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell–derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as “salivary gland–type carcinomas of the thyroid.” Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as “thymic tumors within the thyroid.” There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with
DICER1
mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information.
Background:
TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell ...immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas.
Objectives:
The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC.
Methods:
TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs).
Results:
TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10−4 vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10−4), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04).
Conclusions:
TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.
In the modern era, a pathology report of thyroid carcinoma requires the inclusion of numerous prognostically relevant histopathological features, e.g. the presence and extent of vascular and capsular ...invasion, extrathyroidal extension, the surgical margin status and the characteristics of nodal metastasis. These pathological features are crucial components of the initial risk stratification to determine the need for completion thyroidectomy and/or postoperative radioactive iodine ablation therapy. The current review aims to summarise the diagnostic criteria, the controversies, the prognostic impacts and the challenges of these pathological characteristics, focusing specifically on the parameters that are incorporated into the American Joint Committee on Cancer (AJCC) staging system, the College of American Pathologists (CAP) reporting template, the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines.
This review provides historical context to recent developments in the classification of the follicular variant of papillary thyroid carcinoma (FVPTC). The evolution of the diagnostic criteria for ...papillary thyroid carcinoma is described, clarifying the role of molecular analysis and the impact on patient management.
A PubMed search using the terms "follicular variant" and "papillary thyroid carcinoma" covering the years 1960 to 2016 was performed. Additional references were identified through review of the citations of the retrieved articles.
The encapsulated/well-demarcated, noninvasive form of FVPTC that occurs annually in 45,000 patients worldwide was thought for 30 years to be a carcinoma. Many studies have shown almost no recurrence in these noninvasive tumors, even in patients treated by surgery alone without radioactive iodine therapy. The categorization of the tumor as outright cancer has led to aggressive forms of treatment, with their side effects, financial costs, and the psychological and social impacts of a cancer diagnosis. Recently, the encapsulated/well-demarcated, noninvasive FVPTC was renamed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. The new terminology lacks the carcinoma label, enabling clinicians to avoid aggressive therapy.
By understanding the history of FVPTC, future classification of tumors will be greatly improved.
In the upcoming World Health Organization fifth edition classification of endocrine tumors, there were several major changes related to high grade follicular-derived thyroid carcinoma (HGFCTC) and ...anaplastic thyroid carcinoma (ATC) based on emerging evidence about the diagnostic criteria clinical behavior, prognostic factors, and molecular signatures of these tumors. In this review, we aim to summarize the major evolutions of HGFCTC and ATC. HGFCTC is a nonanaplastic carcinoma with high grade features (High mitotic count, tumor necrosis). It is subdivided into poorly differentiated thyroid carcinoma diagnosed using the Turin proposal and differentiated high grade thyroid carcinoma. The latter is defined by the presence of the cytoarchitectutal features of well-differentiated thyroid carcinoma (eg, papillae) but harbors elevated mitotic activity and/or tumor necrosis. Poorly differentiated thyroid carcinoma is predominantly RAS -driven and associated with RAI avidity and high propensity for distant metastasis, whereas differentiated high grade thyroid carcinoma is mostly BRAFV600E -driven. ATC may show a wide range of histologic features. Carcinoma of pure squamous phenotype is associated with a high frequency of BRAF V600E mutations and is now considered as a subtype of ATC. There is a stepwise molecular progression from well-differentiated carcinoma to HGFCTC to ATC manifested by 1) early and persistent driver alteration in the MAPK pathway, particularly BRAF V600E and RAS mutations, and 2) gain of secondary aggressive molecular signatures (such as TERT promoter and TP53 mutations) when tumors progress from well-differentiated to high grade to anaplastic carcinoma.
Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of ...therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
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•Upregulation of AXL counteracts PI3Kα inhibition•AXL dimerizes with EGFR and activates the PLCγ-PKC pathway•The EGFR-PLCγ-PKC signaling results in PI3K/AKT-independent activation of mTOR•Inhibition of EGFR, PKC, or AXL reverts resistance to PI3Kα inhibitors
Elkabets et al. find that head and neck and esophageal squamous cell carcinomas refractory to PI3Kα inhibition overexpress AXL. They show that AXL interacts with EGFR to activate PLCγ and PKC, leading to PI3K-independent mTOR activation. Inhibition of EGFR, AXL, or PKC reverts resistance to PI3Kα inhibition.
The follicular variant of papillary thyroid carcinoma usually presents as an encapsulated tumor and less commonly as a partially/non-encapsulated infiltrative neoplasm. The encapsulated form rarely ...metastasizes to lymph node, whereas infiltrative tumor often harbors nodal metastases. The molecular profile of the follicular variant was shown to be close to the follicular adenoma/carcinoma group of tumors with a high RAS and very low BRAF mutation rates. A comprehensive survey of oncogenic mutations in the follicular variant of papillary thyroid carcinoma according to its encapsulated and infiltrative forms has not been performed. Paraffin tissue from 28 patients with encapsulated and 19 with infiltrative follicular variant were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes. There was no difference in age, gender, tumor size and angioinvasion between encapsulated or infiltrative tumors. Infiltrative carcinomas had a much higher frequency of extrathyroid extension, positive margins and nodal metastases than encapsulated tumors (P<0.05). The BRAF 1799T>A mutation was found in 5 of 19 (26%) of the infiltrative tumor and in none of the encapsulated carcinomas (P=0.007). In contrast, RAS mutations were observed in 10 of 28 (36%) of the encapsulated group (5 NRAS_Q61R, 3 HRAS_Q61, 1 HRAS_G13C and 1 KRAS_Q61R) and in only 2 of 19 (10%) of infiltrative tumors (P=0.09). One encapsulated carcinoma showed a PAX8/PPARgamma rearrangement, whereas two infiltrative tumors harbored RET/PTC fusions. Encapsulated follicular variant of papillary thyroid carcinomas have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF>RAS mutations). The molecular profile of encapsulated and infiltrative follicular variant parallels their biological behavior (ie, metastatic nodal and invasive patterns).
Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) ...pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.
We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.
Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.
Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. ...In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC.
Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm
, Ki67 proliferative index ≥ 5%, or tumor necrosis.
Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio HR = 11.490; 95% CI, 3.118 to 32.333;
< .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327;
= .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261;
= .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193;
= .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers.
This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
Background:
The mutated BRAF V600E protein has been specifically detected in papillary thyroid carcinomas (PTCs) using immunohistochemical (IHC) analysis. The clonal origin of PTCs harboring BRAF ...mutations has recently been called into question.
Objectives:
The purpose of this study was 2-fold: (1) to compare BRAF V600E IHC expression in PTCs, poorly differentiated thyroid carcinomas (PDTCs), and anaplastic thyroid carcinomas (ATCs) with DNA mutation analysis; and (2) to study the distribution of BRAF V600E IHC staining within thyroid cancer tissues.
Methods:
Whole sections and tissue microarrays from 31 PTCs, 38 PDTCs, and 22 ATCs were subjected to both mass spectrometry genotyping for the BRAFT1799A mutation as well as IHC staining for BRAF V600E protein.
Results:
Of the 31 PTCs, 16 (52%) showed strong (3+) IHC staining and harbored BRAFT1799A, whereas the remaining 15 (48%) showed absent/faint (0/1+) staining, and were wild type for BRAF (BRAF-wt). Only 5 of 38 (13%) PDTCs harbored mutant BRAF, and these were the only ones with moderate (2+) or 3+ IHC staining. All 14 ATCs with a staining intensity of 3+ harbored BRAFT1799A, whereas the 2 ATCs with 0/1+ staining were BRAF-wt. Six ATCs showed staining of 2+, 5 of which had high background staining. Of those 6 cases, BRAFT1799A was present only in the tumor without background. Homogeneous staining was found in 13 of 14 (93%) PTCs, 3 of 3 (100%) PDTCs, and 12 of 14 ATCs (86%).
Conclusions:
First, absent/faint staining for BRAF V600E correlates perfectly with the lack of the BRAFT1799A mutation, whereas strong staining is highly specific for the BRAFT1799A mutation in PTCs, PDTCs, and ATCs. Moderate staining intensity cannot be relied on and should lead to genotypic analysis. Second, homogeneous staining occurs in the vast majority of cases, demonstrating that the BRAFT1799A mutation is a clonal event in thyroid cancer.
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